gd T cells localize to epithelial sites where they play important roles in tissue homeostasis, wound healing, and protection from malignancy. In the skin, dendritic epidermal T cells (DETC) express a unique, monoclonal gd TCR. DETC monitor neighboring epithelial cells for damage or disease. Following recognition of epithelial distress the DETC respond by the production of growth factors and chemokines that modulate keratinocyte proliferation and migration of inflammatory cells. The antigen(s) that active DETC and drive their function are currently unknown. Since all DETC express an identical TCR we hypothesize that these cells will recognize a single or limited set of related antigens. In contrast to ab T cell recognition of specific pathogen peptides presented by MHC molecules, we propose that DETC will see distress-induced self antigens that are commonly expressed after any type of damage or disease. This would allow the population to be broadly specific for local trauma instead of mono-specific for a particular pathogen. This proposal will test these hypotheses through analysis of the antigen specificity of DETC. We have developed new tools for DETC antigen detection that will be used in studies to identify the DETC antigen(s) along with biochemical strategies for antigen characterization. The skin is an important barrier to the outside world and is constantly under assault by pathogens, trauma, and UV irradiation as well as being a common site for malignancy. Information gained about antigens for DETC may lead to the development of a new paradigm for intraepithelial gd T cell antigen recognition and provide tools for future exploitation of the wound healing and lytic properties of these cells to fight malignancy and accelerate repair of chronic wounds. PUBLIC HEALTH RELEVANCE: Narrative Skin gd T cells play important roles in tissue homeostasis, eradication of tumors and wound healing. Identification of the antigens that activate these cells is necessary in order to exploit these cells to fight skin malignancies and increase the efficiency of repair of chronic, non-healing wounds.